Stem cells are a type cells that could be a source for the replacement of damaged or diseased tissues, and embryonic stem cells (ESCs) are a type of stem cells attracting particular interest. It has been previously shown that embryonic stem cells have the capacity to differentiate into many different cell types including heart, bone, neurons, liver tissue, and the like, both in vitro and in vivo. The differentiation potential of these cells has created substantial interest, since embryonic stem cells can thus provide a resource for replacing diseased cells for regenerating purposes.
ESCs are pluripotent cells which are derived from the inner cell mass of a blastocyst. The unique characteristics of ESCs are their capacities to regenerate themselves and to be capable of developing into various cell types of all three embryonic germ layers, ectoderm, mesoderm and endoderm, under appropriate environments. Such differentiated cell types include, but are not limited to, muscle, nerve, heart, liver, bone and blood. The potential of ESCs, induced pluripotent stem cells (iPSCs), adult or tissue specific stem cells and the like to grow into specialized cells attracts interest for research and disease treatment using these cells. The clinical application of stem cells involves harvest of the cells and transplantation of cells into failing organs to restore the function of the organs with or without prior in vitro differentiation.
Adult cardiomyocytes retain little, if any, ability to replicate, thus, heart failure is principally a disease of cardiomyocyte loss. No stem cell therapies to date have yielded significant replacement. Rather, transplanted cells, if they persist, produce endothelial cells or fibroblasts, and their reported ameliorating effects on heart function are probably the consequence of improvements in contractility, perfusion or other impaired processes. Replacement strategies by transplantation or stimulation of endogenous regeneration have been hypothesized. Whether endogenous cardiomyocyte stem cells exist and can be mobilized remains controversial, although a few populations have been proposed. Cardiomyocytes have potential in restoring heart function after myocardial infarction or in heart failure. Human embryonic stem cells (hESCs) are a potential source of transplantable cardiomyocytes but detailed comparison of hESC-derived cardiomyocytes with primary human cardiomyocytes is necessary before transplantation into patients becomes feasible.
While a clear alternative is to use hESCs, their cardiomyocyte yields are currently low. Generating sufficient new myocytes is a major obstacle when 25% of the ˜4 billion cardiomyocytes in the average left ventricle are lost in infarction-induced heart failure. Transplanted cell survival is currently about 5%, thus improving replication of committed precursors either pre- or post-implantation is essential. Interestingly, transplanted hESC-derived cardiomyocytes tend to retain some proliferative capacity, perhaps due to their relative immaturity; however, the number of engrafted cells remains small in all studies to date, thereby reinforcing the need for molecules that promote cell division.
The American Diabetes Association estimates that there are currently 5 million people in the United States with confirmed diabetes, and over 10 million at risk. The cost of this disease and its sequelae to the American economy is staggering. Care of diabetics consumes a total of $98 billion per year, accounting for one of every seven healthcare dollars spent in the U.S. There are 24,000 new cases of diabetes-caused blindness caused by diabetes each year. Diabetes is the leading cause of kidney failure, contributing about 40% of new dialysis patients. Diabetes is also the most frequent cause of lower limb amputation, with 56,000 limbs lost to diabetes each year. The per capita health care costs incurred per diabetic person is $10,071 annually, compared with $2,669 for non-diabetics.
Type I diabetes mellitus (also known as insulin-dependent diabetes) is a severe condition accounting for 5-10% all diabetics. The pathology arises because the patient's insulin-secreting beta cells in the pancreas have been eliminated by an autoimmune reaction. Under current practice, the condition is managed by regular injection of insulin, constant attention to diet, and continuous monitoring of blood glucose levels to adjust the insulin dosing. It is estimated that the market for recombinant insulin will reach $4 billion by 2005. Of course, the availability of insulin is life-saving for Type I diabetics. But there is no question that the daily regimen of administration and monitoring that diabetics must adhere to is troublesome to the end user, and not universally effective.
Developmental work has been done in several institutions to capitalize on the promise of pluripotent stem cells from the embryo to differentiate into other cell types. Cells bearing features of the islet cell lineage have reportedly been derived from embryonic cells of the mouse.
It is necessary to develop new paradigms to differentiate human pluripotent cells into fully functional differentiated cell types.